Abstract 344: Subpopulations of lung neuroendocrine cells mirror neuronal development.

Pulmonary neuroendocrine cells (PNECs) which comprise less than 1% of airway epithelium were recently shown to be the cell of origin for small cell lung cancer (SCLC). SCLC is the most aggressive form of human lung cancers and characterized by early dissemination or metastases and neuroendocrine features. We used immunohistochemistry (IHC) and animal models in order to delineate the cellular hierarchy of PNEC potentially leading to cancer. PNECs were first identified in the early lung development (E12.5) as positive for the proneural basic helix-loop-helix transcription factor Achaete-scute homolog-1 (Ascl1) which is pivotal for PNEC differentiation and highly expressed in SCLC. Later in the development (E16.5) and in adulthood, PNECs coexpressed Ascl1 and calcitonin gene-related peptide (CGRP), a primary neuropeptide in mouse lung. Interestingly, we showed that doublecortin (DCX), a marker of immature migrating neurons, is transiently expressed in PNECs during the early development. Later in the development (E16.5), we observed a subpopulation expressing the neural-specific β3-tubulin (TUBB3), a neuronal marker. We also observed that neural cell adhesion molecule (NCAM), a marker of SCLC, is transiently expressed in a low number of PNECs in the late embryonic period. In parallel, using the transgenic CC10-hASH1 mouse model, where Ascl1 is overexpressed in non-neuroendocrine airway epithelial cells, we determined that it is not sufficient to induce neuroendocrine differentiation or expression of DCX, TUBB3 and NCAM. We conclude that Ascl1, DCX and TUBB3 are consecutively expressed in PNECs during development, similarly to the pattern observed during neuronal development. However, Ascl1 expression seems to be maintained even in the mature PNECs unlike in the mature neurons where it is turned off. On the other hand, NCAM expression in PNECs is transient and maybe reactivated during the instance of SCLC. To establish the relationships between the different PNEC populations and Ascl1 expression, we are currently evaluating Cre-dependent conditional Ascl1 deletion in mouse lung. Further work will be necessary to address the functional potential of the PNEC subpopulations in tumorigenesis. Citation Format: Florent Suau, Ilona Linnoila, Xu Naizhen. Subpopulations of lung neuroendocrine cells mirror neuronal development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 344. doi:10.1158/1538-7445.AM2013-344